Method of manufacturing pharmaceutical articles

ABSTRACT

The invention relates to a process of preparing pharmaceutical closures for containers made of flexible polymeric materials which are suitable to be filled with parenterally administerable fluids prior to their sealing and sterilization. The process involves a specific relaxation period for the elastomer material of the closure which thereby can settle and develop resealing characteristics. The closures will have an excellent resealing capacity after being penetrated by a piercing device for establishing fluid communication with the container, even after multiple entries into the container.

This application is a CIP of PCT/SE98/00294, filed Feb. 19, 1998 and adivisional of U.S. application Ser. No. 09/027,210 filed Feb. 20, 1998which in turn claims priority to Swedish application no. 9700597.9 filedFeb. 20, 1997 and U.S. Provisional Application No. 60/038,523 filed Feb.26, 1997, now abandoned all of which are herein incorporated byreference.

FIELD OF INVENTION

The invention relates to a process of preparing pharmaceutical closuresfor containers made of flexible polymeric materials which are suitableto be filled with parenterally administerable fluids prior to theirsealing and sterilization. More particularly, closures are preparedwhich have an excellent resealing capacity after being penetrated by apiercing device for establishing fluid communication with the container,even after multiple entries into the container.

BACKGROUND OF THE INVENTION

The efforts of providing containers of polymeric materials forparenterally administerable products which are sterilizable after beingfinally filled and assembled, but also safe from migration ofpotentially hazardous agents and easy to recycle, have been previouslydisclosed in the International patent applications WO 95/08317, WO97/37628 and WO 97/39952.

EP 0 097 054 (Hantakki Oy) discloses a flexible bag for medical fluidsprovided with an injection port which has a closure comprising ashielded resilient pierceable pad which reseals after penetration andwhich also may be protected from the stored fluids. This type of closurehas the drawback in that it is quite complicated to assemble fromdifferent parts in the moment of sealing the ports and therefore is lesssuitable in an aseptic environment.

U.S. Pat. No. 4,303,067 (American Hospital Supply Corp.) describes anadditive port for a medical bag through which medicals can be suppliedby an injection device. The port has a puncturable, reasealable plugmade of an elastomer. Nothing is disclosed about the resealing capacityor the sterilizability of the closure.

U.S. Pat. Nos. 4,975,308 and 5,247,015 describe molded stoppers forblood tubes made of a halobutyl rubber dispersed in a mixture ofpolyolefins and a thermoplastic elastomer. No disclosures are givenherein about their resealing capacity after needle penetration or theircapacity of being heat sterilized.

There are numerous other citations in the literature of closures forpharmaceutical containers of various types, both made of glass or ofpolymeric materials which are disclosed to be suitable to seal storedfluids for parenteral administration. Generally, it is a requirementfrom medical authorities that such closures must be capable ofmaintaining a barrier against the environment, both during sterilizationby steam and during subsequent long term storage. It is also requiredthat this type of closures shall be capable to reseal spontaneously andimmediately after the withdrawal of a penetrating needle. They must alsohave a resealing capacity after multiple entries by penetrating needle,a cannula or a similar penetrating device suitable for collecting fluidfrom the container or for adding a component to be mixed with thecontents of the container. An improper resealing of the closure afterpenetration potentially will waste the integrity of stored fluids byproviding a channel for microbial growth into the container. It is alsoa requirement that the container must not leak when its closure ispenetrated during fluid connection, for instance during infusion to apatient through a cannula. Furthermore, the closure must be compatiblewith stored fluids and no migration of potentially hazardous agents fromany of its parts is allowed. The closure must also withstandconventional sterilization processes including autoclavation at 121° C.and sterilization by irradiation without losing any of its sealingcapacity. It is also a requirement set by an increasing amount ofmedical authorities that each authorized container must be possible torecirculate and its therefore a demand that empty containers shall bepossible to dispose without laborious disassembling and sorting of partsfor individual recycling processes.

In the aforementioned International patent application WO 97/39952,ports for containers storing parenterally administerable fluids havingclosures generally fulfilling several of these requirements aredisclosed which are designed to have all important parts correctlysterilized by pressurized steam in the autoclave. These closurestypically comprise a frame or carrier part for a penetrable plug,wherein said carrier is adapted to seal an orifice by weak seal weldingsor by being clamped in the orifice of the container. The penetrable plugof the closure is intended to be pierced by a device for establishingfluid communication with the container e.g. an injection syringe. Asdescribed in the previously mentioned Swedish patent application SE9601540-9, such a closure can be produced in a two-color mold processwherein the generally sleeve formed carrier first is molded ofthermoplastic material in a desired shape to sealingly fit with acontainer orifice, whereupon liquefied thermoplastic elastomer isinjected into the sleeve to form the penetrable plug. These closures arehighly advantageous over prior art sealing means by their simpleproduction process and their comparatively simple assembly in a sealingposition in a container orifice without extra time consuming steps,where their various parts must be assembled to form an adequate sealingdevice.

It is, however, a considerable technical problem to repeatedlymanufacture this type of closures under conditions such that theelastomer plug obtains suitable characteristics of being resealableafter multiple entries into the container by piercing devices, while itat also at the same time must form sealing adhesive bondings along thecontact surface with the inner periphery of the carrier, so the two-partclosure perfectly may seal against the environment. In particular, ithas been connected with problems to find a reliable process which isreproducible in giving the penetrable plug specific resealingcharacteristics in a conventional two-part molding technique. This typeof closure must also preferably be capable of forming a reliable sealwith the container orifice, for example by forming weak seal weldings,as described in the above mentioned International patent application WO95/08317.

DESCRIPTION OF INVENTION

It is an object of the present invention to provide a process formanufacturing pharmaceutical closures with a pierceable plug of anelastomeric material which safely reseals itself after being piercedwith a syringe, a cannula or similar device capable of adding orwithdrawing a fluid from a medical container.

It is also an object of the invention to provide a process which ishighly reproducible in giving the pierceable plugs a resealing capacityafter being pierced at least according to the DIN 58 363 part 15standard.

It is a further object of invention to provide such a method ofpreparing pierceable plugs in a two-part injection molding technique toform adhesive bondings of an elastomer part and a carrier part in ahighly reliable manner without employing any bonding agents and with lowrisk of contamination, while at the side time avoiding the formation ofcavities between the two parts.

Another object of the present invention is the provision ofpharmaceutical closures which consists polyolefins to such an extentthat both the closure and the polyolefinic container body can berecirculated together without being disassembled and separatelycollected, while having a resealing capacity at least according to theDIN 58 363 part 15 standard.

A further object of the present invention is to provide pharmaceuticalclosures with the mentioned resealing capacity which are possiblesterilize by high pressure steam (autoclavation) or by irradiation in asingle process after being assembled with the container and maintain itsintegrity and other important characteristics, while being compatiblewith substantially all infusion fluids including lipophilic fluids likelipid emulsions without causing migration of potentially toxic agents.

A still further object of the present invention is to providepharmaceutical closures of a two-part comprising a pierceable plug of anelastomer in a carrier part wherein said carrier part is provided withmeans for deleting cavities formed during the manufacturing process.

The present invention is directed to a method of preparingpharmaceutical closures of a two-part type comprising a generallysleeve-formed carrier made of a polyolefinic material coaxiallyenclosing a generally cylindrical elastomeric penetrable plug. Thecarrier part is separately formed in a molding process, whereupon heatedelastomer is introduced into said carrier in an injection moldingprocess with conventional injection molding tools, at a high pressure toform a penetrable plug. A characteristic feature of the method is thatit allows for a relaxation period of the thermoplastic material in theinjection molding tool to settle and develop its resealingcharacteristics. The relaxation is generated by letting the highpressure be lowered to a reduced overpressure level during a controlledrelaxation period and by subsequently gradually reducing theoverpressure to an atmospheric pressure over a prolonged cooling period.Another feature of the method is to, before the elastomer is introduced,cooling the carrier from its high forming temperature to a temperaturewell above room temperature but not exceeding about 60° C.

By such a method suitable adhesive bondings are provided in the contactsurface between the carrier and the elastomer plug while the elastomermaterial is allowed to relax in a controlled manner. The relaxationperiod and subsequent cooling and settling period leads to a relaxationon a molecular level which surprisingly enhances the recoverycharacteristics of the elastomer material, so it obtains an excellentresealing capacity.

The elastomer is heated to fluidity, or to reasonable flowcharacteristics, which typically means to a temperature exceeding 180°C., dependent on the selected thermoplastic elastomer. By the specificfeatures of the carrier part, more closely described below, air will bespontaneously evacuated from its inside when the heated elastomer isinjected under high pressure which obstructs the formation of aircavities or bubbles in the elastomer and in the region between theelastomer and the carrier.

After the high pressure introduction in the carrier, the pressure isreleased to a lower level of overpressure and during this relaxationperiod more heated elastomer can be reintroduced into the carrier tocompensate for any shrinking effect, when the elastomer is cooled.Preferably, to obtain the suitable resealing characteristics with saidmethod, the relationship between the magnitude of the reduced overpressure and high pressure is about between 1:2 and 1:5, a preferredrelationship is about 1:3.

The initial high pressure level in the injection molding is preferablyat least about 20 bar, but not exceeding about 50 bar. The reducedoverpressure exerted during the relaxation period is preferably not morethan about 17 bar.

Preferably the high pressure step and the subsequent relaxation step hasabout the same duration. The high pressure step, has a preferredduration of about 3 to 5 seconds, and most preferably about 4 seconds,while the controlled relaxation period has a duration of more than onesecond, but does preferably not exceed five seconds, most preferably ithas duration of about 3 three seconds. The subsequent cooling periodpreferably is preferably is longer than the sum of the high pressurestep and the controlled relaxation step. Preferably the cooling step isabout 10 to about 20 seconds.

The method according to the present invention can be performed byconventional injection molding equipment. The person skilled in thisfield of technology will have no difficulties in finding suitableequipment to mold the carrier part in a desired shape and to transfer itin the protected environment of a two-part molding station and fill itwith an injected heated, flowing elastomer under high pressure.

The carrier is preferable essentially consisting of medical gradepolyolefins which may be compounded with a fraction of thermoplasticelastomer and shall generally be capable of sealing the containerorifice, for example by forming weak seal weldings with a compatiblematerial of the container orifice. Preferably, the polyolefin ispolypropylene or polyethylene based which means that it essentiallyconsists of polypropylene or polyethylene, optionally with a fractioncopolymerized ethylene or propylene. Various medical grades of purepolypropylene or polyethylene are also conceivable materials.

The elastomer material for production of the resealable plug preferablycomprises a polyolefin compatible with the carrier and a thermoplasticelastomer. Suitable commercially available materials are Dynaflex® fromGLS Corp., containing polypropylene and SEBS(styrene-ethylene-butadiene-styrene), Santoprene® containingpolypropylene and EPDM-rubber, Evoprene® from Evode, Cflex andCraiwton®, as well as and various materials containing polyisobutylene(PIB).

The inventive method will specifically be useful for preparingpharmaceutical closures with a penetrable plug made of elastomer whichhas a resealing capacity which fulfills at least the requirements ofstandard norm DIN 58 363 Part 15 that it should be reasealable after apenetration with a 0.6 mm needle without any escape of fluid.

DETAILED DESCRIPTION OF INVENTION

FIG. 1 shows a schematic side-view of a pharmaceutical closure accordingto the present invention.

Referring to FIG. 1 a carrier, frame-like construction 10 is molded in aconventional equipment from polypropylene granules of a medical grade.The carrier is generally is sleeve-formed and has an upper generallycylindrical part 11 designated to face the environment in its sealingposition and lower generally cylindrical part 12 designated to front thestored fluids of a container. The upper part is provided with a frame 13to be filled with an elastomer to form the penetrable plug. The lowerpart may be provided with means for facilitating the sealing connectionwith an orifice of the container (not shown), such as corresponding,flanges or protrusions fitting with the container. A thin partitionmembrane 14 of the carrier seals off the elastomer plug from the storedliquid to prevent from potential extraction or migration of compoundsfrom the elastomer materials to the stored fluids. The carrier can beprovided with a means for evacuation of any undesired cavities of airgenerated during the molding of the elastomer. This means preferablycomprise a narrow annular channel 15,16 extended axially along the innerperiphery its upper part 11, as schematically is shown in FIG. 1. Thechannel serves as a means of transporting air cavities or bubbles to theatmosphere. Such air cavities may appear during the injection of theliquefied elastomer into the carrier. For this reason, the channel isconnected to at least one shallow groove 17 which is radially extendedin the upper surface of the partition 14. This arrangement will lead tothat air in the form of voids or bubbles will be directed out of theelastomer mold by means of the grooves in communication with thechannels. The dimensions of the channels and grooves generally are smalland typically substantially less than a 1 mm, preferably less than 0.5mm and they are incorporated in the carrier part during its manufactureby molding by adding an appropriate design to the forming steel. Suchforming measures are well known to the skilled person and will not bediscussed here in more detail.

In the manufacturing process, the carriers are transferred from itsproduction site to a position for two-part injection molding withelastomer during a short limited time (less than 10 seconds) incontrolled atmosphere to protect them from contamination. During thetransfer, the carrier is cooled from its molding temperature of about250° C. to a temperature of about 80° C. During the injection molding, ahigh pressure of about 20-50 bar is exerted and liquefied Dynaflex®(thermoplastic elastomer containing polypropylene and SEBS) heated toabout 200 to 220° C. is injected and filled in the frame 13 of thecarrier, having a temperature of about 60° C. in order to form suitableadhesive bondings. The pressure is then released to a lower level ofoverpressure, not higher than about 17 bars for about 3 seconds for arelaxation period, before the pressure is gradually released to thelevel of the ambient atmosphere during about 20 seconds in a coolingperiod. The carrier preferably is filled to about 95% with elastomerfrom the beginning in the high pressure period to compensate for theshrinking of the material and can optionally be refilled with elastomerin a controlled manner during the relaxation period. The closures arethen released, from the injection molding equipment and may be collectedand transferred for use with selected containers in a filling andsealing arrangement. According to the embodiment where the carriercomprises the channel for directing air away from the elastomer mold, itis preferred that the main cavity of carrier part is first filled withelastomer, whereupon the channel is filled in a final stage.

The two-part closures made with this process have an excellent resealingcapacity even after being penetrated several times by sharp objects,like needles and cannulas for introduction or removal of fluid to orfrom containers where they are sealingly fitted. As evident from thefollowing example the resealing capacity exceeds the requirements set onthe standard norm DIN 58 363 part 15 for infusion containers andaccessories.

It should be understood that it is possible for the skilled person todepart from the mentioned, specific shape of the closures and specifiedmaterial as well as the process parameters used in this example andstill arrive within the process and articles, as claimed in the appendedclaims.

EXAMPLE

Pharmaceutical closures prepared as described above are inserted tosealing in a corresponding mouth piece of flexible bag type containerfilled with a nominal volume of an aqueous parenteral solution. Thesealed container is sterilized by means of conventional autoclavationand cooled, whereupon the surface assigned for injection of the closureis penetrated with a cannula of 0.8 mm diameter. After removal of thecannula the injection point is subjected to an internal pressure of 20kPa for 10 seconds, in order to determine the leak resistance at theinjection point. No leak is detected. These measures are repeated twoconsecutive times for the same closure without any leaks.

In order to determine the spike retention in a closure according to thepresent invention, a spike conventional in infusion sets is insertedthrough its injection point to establish fluid connection with acontainer sealed with said closure. The inserted spike was thensubjected to a downwards force of 10 N for 5 hours. The spike remainedimmobilized in the closure and no leakage of solution was detected.

In a second test set up to determine the spike retention under pressurein a closure according to the present invention, a spike conventional ininfusion sets is inserted through its injection point to establish fluidconnection with a container sealed with said closure. The flexiblecontainer was then subjected to an internal pressure of about 20 kPa for15 seconds. No leakage of solution was detected.

What is claimed is:
 1. A method of preparing two-part pharmaceuticalclosures comprising a sleeve-formed carrier made of a polyolefinicmaterial coaxially enclosing a cylindrical elastomeric penetrable plug,wherein a carrier part is separately formed in a molding process andcomprises a narrow annular channel extending axially along the innerperiphery of an upper part, the annular channel being connected by atleast one shallow groove which is radially extended in the upper surfaceof a partition of the carrier, whereupon heated elastomer is introducedinto said carrier in an injection molding process at a high pressure toform a penetrable plug and whereupon it is allowed a relaxation periodfor the elastomer material to settle and develop its resealingcharacteristics.
 2. A method according to claim 1 characterized by arelaxation period comprising: (i) lowering said high pressure to areduced overpressure level during a controlled relaxation period; andsubsequently (ii) gradually reducing said overpressure to an atmosphericpressure during a controlled cooling period.
 3. A method according toclaim 2 characterized by reintroducing heated elastomer during saidrelaxation period to compensate for its shrinking.
 4. A method accordingto any of claim 2 characterized by supporting said carrier by asupporting tool during said cooling period.
 5. A method according to anyof claim 2 characterized in that the high pressure is at least 20 bar,but not exceeding 50 bar.
 6. A method according to any of claim 2characterized in that the reduced overpressure is not exceeding 10 bar.7. A method according to any of claim 2 characterized in that the heatedelastomer is subjected to vacuum before being introduced to thepressurized molding process.
 8. A method according to any of claim 2characterized in that said controlled relaxation period is at least onesecond, but not more than five seconds.
 9. A method according to any ofclaim 2 characterized in that said cooling period lasts about 20seconds.
 10. A method according to any of claim 1 characterized in thatthe carrier comprises polypropylene and is capable of forming weak sealweldings with a container orifice.